Indolyl-3-glyoxylic acid derivatives having therapeutically valuable properties

ABSTRACT

The object of the invention is then to widen the field of use of N-substituted indole-3-glyoxylamides and thus to enrich the available pharmaceutical wealth. The possibility of a lower, longer-lasting and better-tolerable medication for the class of substances having antitumor action described in German Patent Application 19814 838.0 should thus be opened up. In particular, the disadvantageous development of resistance, as is known of many antitumor agents, should be circumvented.

[0001] The invention relates to the further advantageous embodiment ofthe German Patent Application indole-3-glyoxylamides having thereference 19814 838.0.

[0002] In connection with chemotherapy in the case of oncoses, thegreatest problems result due to the occurrence of pharmaceuticalresistance on the one hand and due to the serious side effects of theseagents on the other hand.

[0003] In addition, it is known that after reaching a certain size manyprimary tumors prematurely tend to metastasis formation via the bloodstream and lymphatic tracts. The progressive process of tumor invasionand the formation of metastases is the most frequent cause of death ofthe cancer patients.

[0004] There are various approaches for explaining this spread, interalia enhanced angiogenesis, increased extracellular matrix degradation,tumor cell migration and modulation of cell adhesion. These factors canalso interact but to date are only partially resolved.

[0005] The metastatic spread of a tumor is usually accompanied by poorprognoses in tumor treatment. The prerequisite for metastatic spread isthe detachment of cells from the primary tumor, the migration of cellsto the blood vessels, invasion into the blood vessels and invasion ofthe cells from the blood vessels into other tissue.

[0006] An inhibitory action of certain oncostatic agents such astamoxoifen [sic] on the migration and invasion of cancer cells is known[J Clin Endocrinol Metab Januaru 1995; 80(1): 308-13]

[0007] The inhibition of tumor cell invasion by verapamil has beenreported [Pigment Cell Res December 1991; 4(5-6): 225-33.]

[0008] The influence of melantonin [sic] on invasive and metastaticproperties of MCF-7 human breast cancer cells has been reported [Cancerres Oct. 1, 1998; 58(19): 4383-90]

[0009] In the published PCT Application WO 96/23506, the overcoming ofpharmaceutical resistance in certain tumor pharmaceuticals wasdemonstrated as a result of the gene amplification of the multi-drugresistance gene (MDR gene) brought about by such oncostatic agents.

[0010] Oncostatic agents such as vincristine and Taxol furthermore havea not inconsiderable neurotoxicity, which proves disadvantageous inchemotherapy.

[0011] The object of the invention is then to widen the field of use ofN-substituted indole-3-glyoxylamides and thus to enrich the availablepharmaceutical wealth. The possibility of a lower, longer-lasting andbetter-tolerable medication for the class of substances having antitumoraction described in German Patent Application 19814 838.0 should thus beopened up. In particular, the disadvantageous development of resistance,as is known of many antitumor agents, should be circumvented.

[0012] Moreover, development and spread of the tumor due to metastasesshould be counteracted.

[0013] According to more recent knowledge, as angiogenesis is obviouslyresponsible for tumor growth and the development of metastases, theproperty of angiogenesis inhibition represents a further advantageouspharmaceutical potential, for example, in cancer therapy.

[0014] The increase in action achieved with the N-substitutedindole-3-glyoxylamides should more effectively shape pharmaceuticalconsumption in tumor therapy. Moreover, it should be possible to shortenthe period of treatment and to extend it in therapy-resistant cases. Inaddition, relapses and metastases should be restricted or prevented andthus the survival period of the patients additionally increased. The aimis to develop medicaments which can intervene in the process ofmetastatic spread.

[0015] It has surprisingly been found that the N-substitutedindole-3-gloxylamides [sic] described in German Patent Application 19814838.0, of the general formula 1 described below, which are suitable forthe treatment of oncoses, further have those advantageous properties fortumor treatment which can extend their area of use.

[0016] The invention relates to the use of N-substitutedindole-3-gloxylamides [sic] according to claim 1 general formula 1a fortumor treatment in particular in the case of pharmaceutical resistanceand metastasizing carcinoma and for the suppression of metastasisformation, and also as angiogenesis inhibitors,

[0017] where the radicals R, R₁, R₂, R₃, R₄ and Z have the followingmeaning:

[0018] R=hydrogen, (C₁-C₆)-alkyl, where the alkyl group can be mono- orpolysubstituted by the phenyl ring and this phenyl ring for its part canbe mono- or polysubstituted by halogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, by carboxyl groups, carboxyl groups esterified withC₁-C₆-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups,ethoxy groups, benzyloxy groups and by a benzyl group which is mono- orpolysubstituted in the phenyl moiety by (C₁-C₆)-alkyl groups, halogenatoms or trifluoromethyl groups,

[0019] R is further the benzyloxycarbonyl group (Z group) and thetertiary-butoxycarbonyl radical (BOC radical), furthermore the acetylgroup.

[0020] R₁ can be the phenyl ring, which is mono- or polysubstituted by(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, cyano, halogen, trifluoromethyl,hydroxyl, benzyloxy, nitro, amino, (C₁-C₆)-alkylamino,(C₁-C₆)-alkoxycarbonylamino and by the carboxyl group or by the carboxylgroup esterified with C₁-C₆-alkanols, or can be a pyridine structure ofthe formula 2 and its N-oxide [sic]

[0021] and its N-oxide, where the pyriding structure is alternativelybonded to the ring carbon atoms 2, 3 and 4 and can be substituted by thesubstituents R₅ and R₆. The radicals R₅ and R₆ can be identical ordifferent and have the meaning (C₁-C₆)-alkyl and the meaning(C₃-C₇)-cycloalkyl, (C₁-C₆)-alkoxy, nitro, amino, hydroxyl, halogen andtrifluoromethyl and further are the ethoxycarbonylamino radical and thegroup carboxyalkyloxy in which the alkyl group can have 1-4 C atoms.

[0022] R₁ can further be a 2- or 4-pyrimidinyl heterocycle, where the2-pyrimidinyl ring can be mono- or polysubstituted by the methyl group,furthermore are [sic] the 2-, 3-, and 4- and 8-quinolyl structuresubstituted by (C₁-C₆)-alkyl, halogen, the nitro group, the amino groupand the (C₁-C₆)-alkylamino radical, are [sic] a 2-, 3- and [sic]4-quinolylmethyl group, where the ring carbons of the pyridylmethylradical of the quinolyl group and of the quinolylmethyl radical can besubstituted by (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, nitro, amino and (C₁-C₆)-alkoxycarbonylamino.

[0023] R₁, in the case in which R=hydrogen, the methyl or benzyl groupand the benzyloxycarbonyl radical (Z radical), the tert-butoxycarbonylradical (BOC radical) and the acetyl group, can furthermore be thefollowing radicals:

[0024] —CH₂COOH; —CH(CH₃)—COOH; —(CH₃)₂—CH—(CH₂)₂—CH—COO—;H₃C—H₂C—CH(CH₃)— CH(COOH)-[sic]; HO—H₂C—CH(COOH)—; phenyl-CH₂—CH(COOH)—;(4-imidazolyl)-CH₂—CH—(COOH)—; HN═C(NH₂)—NH—(CH₂)₃—CH(COOH)—;H₂N—(CH₂)₄—CH(COOH)—; H₂N—CO—CH₂—CH—(COOH)—; HOOC—(CH₂)₂—CH (COOH)—;

[0025] R₁, in the case in which R is hydrogen, the Z group, the BOCradical, the acetyl or the benzyl group, can furthermore be the acidradical of a natural or unnatural amino acid, e.g. the α-glycyl, theα-sarcosyl, the α-alanyl, the α-leucyl, the α-isoleucyl, the α-seryl,the α-phenylalanyl, the α-histidyl, the α-prolyl, the α-arginyl, theα-lysyl, the α-asparagyl and the α-glutamyl radical, where the aminogroups of the respective amino acids can be present unprotected or canbe protected. A possible protective group of the amino function is thecarbobenzoxy radical (Z radical) and the tert-butoxycarbonyl radical(BOC radical) as well as the acetyl group. In the case of the asparagyland glutamyl radical claimed for R₁, the second, unbonded carboxyl groupis present as a free carboxyl group or in the form of an ester withC₁-C₆-alkanols, e.g. as a methyl, ethyl or as a tert-butyl ester.

[0026] Furthermore, R₁ can be the allylaminocarbonyl-2-methylprop-1-ylgroup.

[0027] R and R₁ can further form, together with the nitrogen atom towhich they are bonded, a piperazine ring of the formula III or ahomopiperazine ring, provided R₁ is an aminoalkylene group, in which

[0028] R₇ is an alkyl radical, is a phenyl ring which can be mono- orpolysubstituted by (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, halogen, the nitrogroup, the amino function and by the (C₁-C₆)-alkylamino group. R₇ isfurthermore the benzhydryl group and the bis-p-fluorobenzylhydryl [sic]group.

[0029] R₂ can be hydrogen and the (C₁-C₆)-alkyl group, where the alkylgroup is mono- or polysubstituted by halogen and phenyl, which for itspart can be mono- or polysubstituted by halogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, carboxyl groups, carboxyl groups esterified withC₁-C₆-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups,ethoxy groups or benzyloxy groups. The (C₁-C₆)-alkyl group counting asR₂ can further be substituted by the 2-quinolyl group and the 2-, 3- and4-pyridyl structure, which can both in each case be mono- orpolysubstituted by halogen, (C₁-C₄)-alkyl groups or (C₁-C₄)-alkoxygroups. R₂ is further the aroyl radical, where the aryl moiety on whichthis radical is based is the phenyl ring, which can be mono- orpolysubstituted by halogen, (C₁-C₆) -alkyl, (C₃-C₇) -cycloalkyl,carboxyl groups, carboxyl groups esterified with C₁-C₆-alkanols,trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groupsor benzyloxy groups.

[0030] R₃ and R₄ can be identical or different and are hydrogen,(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, (C₁-C₆)-alkanoyl, (C₁-C₆)-alkoxy,halogen and benzyloxy. R₃ and R₄ can furthermore be the nitro group, theamino group, the (C₁-C₄)-mono or dialkyl-substituted amino group, andthe (C₁-C₆)-alkoxycarbonylamino function or(C₁-C₆)-alkoxycarbonylamino-(C₁-C₆)-alkyl function.

[0031] Z is O and S.

[0032] The designation alkyl, alkanol, alkoxy or alkylamino group forthe radicals R, R₁, R₂, R₃, R₄, R₅, R₆, R₇ is normally understood asmeaning both “straight-chain” and “branched” alkyl groups, where“straight-chain alkyl groups can be, for example, radicals such asmethyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and “branched alkylgroups” designate, for example, radicals such as isopropyl ortert-butyl. “Cycloalkyl” is understood as meaning radicals such as, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl.

[0033] The designation “halogen” represents fluorine, chlorine, bromineor iodine. The designation “alkoxy group” represents radicals such as,for example, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy orpentoxy.

[0034] The compounds can also be employed as acid addition salts, forexample as salts of mineral acids, such as, for example, hydrochloricacid, sulfuric acid, phosphoric acid, salts of organic acids, such as,for example, acetic acid, lactic acid, malonic acid, maleic acid,fumaric acid, gluconic acid, glucuronic acid, citric acid, embonic acid,methanesulfonic acid, trifluoroacetic acid, succinic acid and2-hydroxyethanesulfonic acid.

[0035] Both the compounds of the formula 1 and their salts arebiologically active.

[0036] The compounds of the formula 1 can be administered in free formor as salts with physiologically tolerable acids.

[0037] Administration can be performed orally, parenterally,intravenously, transdermally or by inhalation.

[0038] The invention furthermore relates to pharmaceutical preparationswhich contain at least one of the compounds of the formula 1 or theirsalts with physiologically tolerable inorganic or organic acids and, ifappropriate, pharmaceutically utilizable excipients and/or diluents orauxiliaries.

[0039] Suitable administration forms are, for example, tablets, coatedtablets, capsules, solutions for infusion or ampoules, suppositories,patches, powder preparations which can be employed by inhalation,suspensions, creams and ointments.

[0040] The preparation processes for the substances can be taken fromthe examples of German Patent DE 196 36 150 A1.

[0041] The therapeutically valuable properties found relate specificallyto the following advantages:

[0042] no development of resistance was detected

[0043] parameters were detected which are characteristic of theinhibition of metastasis formation (migration)

[0044] parameters were found which confirm the inhibition ofneovascularization (angiogenesis)

[0045] in various models, it was not possible to find any neurotoxicitywith the N-substituted indole-3-gloxylamides [sic] according to claim 1general formula 1a in contrast to most antitumor preparations

[0046] The development of resistance which is not present is confirmedin the following pharmacological models and cell cultures:

[0047] 1. The cytotoxic activity of D-24851 (see claim 4) on the MDR(multidrug-resistant) leukemia cell line of the mouse L 1210/VCR is notinfluenced in vivo and in vitro. See FIGS. 1, 2 and 3.

[0048] D-24851 (see claim 4) has an unchanged cytotoxic activity againstthe multidrug-resistant mouse leukemia cell subline L1210/VCR incontrast to Taxol, doxirubicin, vincristine or epotholone B [sic].

[0049] Experimental Procedure:

[0050] The mouse leukemia cell lines [sic] L 120 was adapted tovincristine. The unadapted (L 1210) and the adapted (L 1210/VCR) cellswere exposed to cytostatic agents and the cell growth, which wasdetermined by the metabolic activity, was determined (XTT test).

[0051] The curves which connect the XTT datapoints were calculated usinga nonlinear regression program.

[0052] These experimental results were also confirmed in vitro on thehuman resistant LT 12/MDR cell line see FIG. 4.

[0053] 2. The detection of lacking metastasis formation was afforded bymeans of inhibition of migration of MO4 cells. See FIG. 5.

[0054] D-24 851 (see claim 4) inhibits the migration of MO4 cells in adose-dependent manner. From this, an antiinvasive and an antimetastaticaction can be derived for D-24851.

[0055] The migration ability of MO4 cells can be measured in vitro byinoculating cells into the center of a cell culture dish and determiningthe migration by means of radius or the covered area of the cells aftervarious days with and without D-24851. FIG. 4 shows that the migrationof the cells decreases with increasing D-24851 concentration.

[0056] In order to test whether D-24851 also acts antiinvasively, theinvasion of MO4 fibrosarcoma cells into chickens' hearts wasinvestigated. It is also seen here that at a concentration of 260 and1000 nM the invasion is completely inhibited, whereas at lowerconcentrations the invasiveness of the MO4 cells increases. On the basisof these findings, it is seen that D-24851 inhibits both the migrationand the invasion of tumor cells and thereby has a strong antimetastaticpotential.

[0057] 3. From comparison experiments of the compound according to theinvention D-24851 (see claim 4) with vincristine and Taxol on rats,where ataxia, traction and reaction were assessed (see FIG. 6), it isevident that this compound shows no neurotoxic effect, in contrast toTaxol and vincristine.

[0058] Furthermore, in comparison to Taxol and vincristine, D-24851 hasno negative influence on the nerve conduction velocity see FIG. 7.

[0059] This confirms that D-24851, on account of the absentneurotoxicity, has clearly lower side effects than otherchemotherapeutics.

[0060] 4. From further investigations as shown in FIGS. 8 and 9, it isevident that the compound D-25851 (see claim 4) has a potential as anangiogenesis inhibitor. As a result of the physiological relationshipwith tumor growth, angiogenesis inhibitors are simultaneously alsoagents for the inhibition of tumor growth, in that the formation of newblood vessels, which are intended to feed the tumor, is inhibited. Invitro in an antiangiogenesis model on endothelial cells, D-24851 causesa complete inhibition of vascularization, which is not based on acytotoxic effect.

[0061] It can be seen in FIG. 8 that D-24851 almost completely breaks upexisting cell-cell contacts due to 0.1 μMol/l of D 24851 [sic] (seevital staining). Normally, the cells maintain at least partial contact.Cell migration is markedly reduced, many cells are rounded.

[0062] Lethal staining in a monolayer before angiogenesis induction didnot show any increased cell mortality with D-24851. Even in the first 22hours after induction, no increased cell mortality was yet discerniblein comparison with the control. (See lethal staining in FIG. 9, whitepoints)

[0063] The cells originated from human umbilical vein (arterialfunction). They were employed for the investigation in the third andfourth passage. Angiogenesis is triggered by a natural stimulus. Theprimary trigger of endothelial migration is a protein which is expressedto an increased extent in vascularizing tissue. The substances are addedto the culture medium shortly before induction of angiogenesis.

[0064] The concentration for the antiangiogenetic action of D-24851 ismarkedly below the concentration for the cytotoxic activity. As aresult, it is possible to separate the two action qualities (cytotoxicactivity and antiangiogenetic action) from one another.

[0065] Without wanting to restrict the scope of the invention by thefollowing statements, it can be said that doses from about 20 mg up to500 mg daily are possible orally.

[0066] On intravenous administration as an injection or as an infusion,up to 250 mg/day or more can be administered depending on the bodyweight of the patient and individual tolerability.

[0067] As a result of the lacking development of resistance andsuppression of metastasis, a high effectiveness and wide use of theagents for [sic] even in tumor-refractory patients can be expected.

[0068] The antiangiogenesis effect is suitable for additionallysuppressing the spread of the tumor.

[0069] However, the invention also comprises the use of theN-substituted indole-3-gloxylamides [sic] according to claim 1 generalformula 1a in further disorders in which an angiogenesis inhibitoryeffect is functionally desired. (e.g. wound healing)

[0070] In addition, the invention also relates to the fixed or freecombination of the N-substituted indole-3-gloxylamides [sic] accordingto claim 1 general formula 1a with antitumor agents known per se, andalso the replacement of antitumor agents which have become ineffectiveas a result of resistance development by N-substitutedindole-3-gloxylamides [sic] according to claim 1 general formula 1a.

1. Use of N-substituted indole-3-gloxylamides [sic] of the generalformula 1 as antitumor agents according to Main Patent Application 19814 838.0 for tumor treatment in particular in the case ofpharmaceutical resistance and metastasizing carcinoma, and also asangiogenesis inhibitors, with markedly lower side effects in particularmarkedly lower neurotoxicity

where the radicals R, R₁, R₂, R₃, R₄ and Z have the following meaning: Ris hydrogen, (C₁-C₆)-alkyl, where the alkyl group can be mono- orpolysubstituted by the phenyl ring and this phenyl ring for its part canbe mono- or polysubstituted by halogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, by carboxyl groups, carboxyl groups esterified withC₁-C₆-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups,ethoxy groups, benzyloxy groups and by a benzyl group which is mono- orpolysubstituted in the phenyl moiety by (C_(l)-C₆)-alkyl groups, halogenatoms or trifluoromethyl groups, R is further the benzyloxycarbonylgroup (Z group) and the tertiary-butoxycarbonyl radical (boc radical),furthermore the acetyl group. R₁ can be the phenyl ring, which is mono-or polysubstituted by (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, cyano, halogen,trifluoromethyl, hydroxyl, benzyloxy, nitro, amino, (C₁-C₆)-alkylamino,(C₁-C₆)-alkoxycarbonylamino and by the carboxyl group or by the carboxylgroup esterified with C₁-C₆-alkanols, or can be a pyridine structure ofthe formula 2 and its N-oxide [sic]

and its N-oxide, where the pyridine structure is alternatively bonded tothe ring carbon atoms 2, 3 and 4 and can be substituted by thesubstituents R₅ and R₆. The radicals R₅ and R₆ can be identical ordifferent and have the meaning (C₁-C₆)-alkyl and the meaning(C₃-C₇)-cycloalkyl, (C₁-C₆)-alkoxy, nitro, amino, hydroxyl, halogen andtrifluoromethyl and further are the ethoxycarbonylamino radical and thegroup carboxyalkyloxy in which the alkyl group can have 1-4 C atoms. R₁can further be a 2- or 4-pyrimidinyl heterocycle, where the2-pyrimidinyl ring can be mono- or polysubstituted by the methyl group,furthermore are [sic] the 2-, 3-, and 4- and 8-quinolyl structuresubstituted by (C₁-C₆)-alkyl, halogen, the nitro group, the amino groupand the (C₁-C₆)-alkylamino radical, are [sic] a 2-, 3- and [sic]4-quinolylmethyl group, where the ring carbons of the pyridylmethylradical of the quinolyl group and of the quinolylmethyl radical can besubstituted by (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, nitro, amino and(C₁-C₆)-alkoxycarbonylamino. R₁, in the case in which R=hydrogen, themethyl or benzyl group and the benzyloxycarbonyl radical (Z radical),the tert-butoxycarbonyl radical (BOC radical) and the acetyl group, canfurthermore be the following radicals: —CH₂COOH; —CH(CH₃)—COOH;—(CH₃)₂—CH—(CH₂)₂—CH—COO—; H₃C—H₂C—CH(CH₃)—CH(COOH)— [sic];HO—H₂C—CH(COOH)—; phenyl-CH₂—CH(COOH)—; (4-imidazolyl)-CH₂—CH—(COOH)—;HN═C(NH₂)—NH—(CH₂)₃—CH(COOH)—; H₂N—(CH₂)₄—CH(COOH)—;H₂N—CO—CH₂—CH—(COOH)—; HOOC—(CH₂)₂—CH(COOH)—; R₁, in the case in which Ris hydrogen, the Z group, the BOC radical, the acetyl or the benzylgroup, can furthermore be the acid radical of a natural or unnaturalamino acid, e.g. the α-glycyl, the α-sarcosyl, the α-alanyl, theα-leucyl, the α-isoleucyl, the α-seryl, the α-phenylalanyl, theα-histidyl, the α-prolyl, the α-arginyl, the α-lysyl, the α-asparagyland the α-glutamyl radical, where the amino groups of the respectiveamino acids can be present unprotected or can be protected. A possibleprotective group of the amino function is the carbobenzoxy radical (Zradical) and the tert-butoxycarbonyl radical (BOC radical) as well asthe acetyl group. In the case of the asparagyl and glutamyl radicalclaimed for R₁, the second, unbonded carboxyl group is present as a freecarboxyl group or in the form of an ester with C₁-C₆-alkanols, e.g. as amethyl, ethyl or as a tert-butyl ester. Furthermore, R₁ can be theallylamino-carbonyl-2-methylprop-1-yl group. R and R₁ can further form,together with the nitrogen atom to which they are bonded, a piperazinering of the formula 3 or a homopiperazine ring, provided R₁ is anaminoalkylene group, in which

R₇ is an alkyl radical, is a phenyl ring which can be mono- orpolysubstituted by (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, halogen, the nitrogroup, the amino function and by the (C₁-C₆)-alkylamino group. R₇ isfurthermore the benzhydryl group and the bis-p-fluorobenzylhydryl group[sic]. R₂ can be hydrogen and the (C₁-C₆)-alkyl group, where the alkylgroup is mono- or polysubstituted by halogen and phenyl, which for itspart can be mono- or polysubstituted by halogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, carboxyl groups, carboxyl groups esterified withC₁-C₆-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups,ethoxy groups or benzyloxy groups. The (C₁-C₆)-alkyl group counting asR₂ can further be substituted by the 2-quinolyl group and the 2-, 3- and4-pyridyl structure, which can both in each case be mono- orpolysubstituted by halogen, (C₁-C₄)-alkyl groups or (C₁-C₄)-alkoxygroups. R₂ is further the aroyl radical, where the aryl moiety on whichthis radical is based is the phenyl ring, which can be mono- orpolysubstituted by halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, carboxylgroups, carboxyl groups esterified with C₁-C₆-alkanols, trifluoromethylgroups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxygroups. R₃ and R₄ can be identical or different and are hydrogen,(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, (C₁-C₆)-alkanoyl, (C₁-C₆)-alkoxy,halogen and benzyloxy. R₃ and R₄ can furthermore be the nitro group, theamino group, the (C₁-C₄)-mono or dialkyl-substituted amino group, andthe (C₁-C₆)-alkoxycarbonylamino function or(C₁-C₆)-alkoxycarbonylamino-(C₁-C₆)-alkyl function. Z is O and S.
 2. Useof N-substituted indole-3-gloxylamides [sic] according to claim 1general formula 1a for tumor treatment in particular in the case ofpharmaceutical resistance and metastasizing carcinoma, and also asangiogenesis inhibitors, with markedly lower side effects in particularmarkedly lower neurotoxicity

where the radicals R=hydrogen R₁=4-pyridyl, 4-fluorophenyl R₂=benzyl,4-chlorobenzyl, 4-fluorobenzyl, 3-pyridylmethyl, 4-bromobenzyl R₃ andR₄=hydrogen and Z is oxygen.
 3. Pharmaceutical composition for tumortreatment in particular in the case of pharmaceutical resistance andmetastasizing carcinoma, and also as angiogenesis inhibitors, withmarkedly lower side effects in particular markedly lower neurotoxicitycharacterized, in that it contains at least one of the compounds of thegeneral formula 1 or 1a, optionally also they [sic] as acid additionsalts, for example as salts of mineral acids, such as hydrochloric acid,sulfuric acid, phosphoric acid, salts of organic acids, such as, forexample, acetic acid, lactic acid, malonic acid, maleic acid, fumaricacid, gluconic acid, glucuronic acid, citric acid, embonic acid,methanesulfonic acid, trifluoroacetic acid, succinic acid and2-hydrop0xyethanesulfonic acid [sic] and possibly their N-oxides.
 4. Useof N-substituted indole-3-glyoxylamides of the general formula 1 or 1aand their physiologically tolerable acid addition salts for theproduction of antitumor agents for use in particular in the case ofpharmaceutical resistance and metastasizing carcinoma, and also asangiogenesis inhibitors, with markedly lower side effects in particularmarkedly lower neurotoxicity namely in particular the followingcompounds or their salts with physiologically tolerable acids or ifpossible their N-oxides: D 24241 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)-indole-3-yl]glyoxylamide D 24843 N-(pyridin-4-yl)-(1-benzylindole-3-yl)-glyoxylamide D 24850 N-(4-fluorophenyl)-[1-(3-pyridylmethyl)-indole-3-yl]glyoxylamide D 24851 N-(pyridin-4-yl)-[1-(4-chlorobenzyl)-indole-3-yl]glyoxylamide D 25505 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)-indole-3-yl]glyoxylamide HCL [sic]


5. Antitumor agents comprising as active agent one or more N-substitutedindole-3-gloxylamides according to the general formula 1 or 1a andoptionally their physiologically tolerable acid addition salts, for usein particular in the case of pharmaceutical resistance and metastasizingcarcinoma, and also as angiogenesis inhibitors, with markedly lower sideeffects in particular markedly lower neurotoxicity but in particular oneor more compounds according to claim
 4. 6. Antitumor agents for tumortreatment in particular in the case of pharmaceutical resistance andmetastasizing carcinoma, and also as angiogenesis inhibitors, with lowerside effects in particular markedly lower neurotoxicity comprising asactive agent namely in particular D 24241N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)- indole-3-yl]glyoxylamide or itshydrochloride


7. Antitumor agents for tumor treatment in particular in the case ofpharmaceutical resistance and metastasizing carcinoma, and also asangiogenesis inhibitors, with markedly lower side effects in particularmarkedly lower neurotoxicity comprising as active agent namely inparticular D 24843 N-(Pyridin-4-yl)-(1-benzylindole-3-yl) glyoxylamide.


8. Antitumor agents for tumor treatment in particular in the case ofpharmaceutical resistance and metastasizing carcinoma, and also asangiogenesis inhibitors, with markedly lower side effects in particularmarkedly lower neurotoxicity comprising as active agent and namely inparticular D 24850 N-(4-Fluorophenyl)-[1-(3-pyridylmethyl)-indole-3-yl]glyoxylamide


9. Antitumor agents for tumor treatment in particular in the case ofpharmaceutical resistance and metastasizing carcinoma, and also asangiogenesis inhibitors, with markedly lower side effects in particularmarkedly lower neurotoxicity comprising as active agent and namely inparticular comprising as active agent comprising as active agent D 24851N-(Pyridin-4-yl)-[1-(4-chlorobenzyl)- indole-3-yl]glyoxylamide


10. Antitumor agent for tumor treatment in particular in the case ofpharmaceutical resistance and metastasizing carcinoma, and also asangiogenesis inhibitors, with markedly lower side effects in particularmarkedly lower neurotoxicity comprising as active agent comprising asactive agent one or more N-substituted indole-3-gloxylamides accordingto the general formula 1 or 1a and optionally their physiologicallytolerable acid addition salts and, if possible, N-oxides, but inparticular one or more compounds according to claim 4 and 6 to 8 and apharmaceutically utilizable excipient and/or diluent or auxiliary in theform of tablets, coated tablets, capsules, solutions for infusion orampoules, suppositories, patches, powder preparations which can beemployed by inhalation, suspensions, creams and ointments.
 11. Use ofN-substituted indole-3-glyoxylamides of the general formula 1 or 1a andtheir physiologically tolerable acid addition salts as angiogenesisinhibitors namely in particular of the following compounds or theirsalts with physiologically tolerable acids or if possible theirN-oxides: D 24241 N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-indole-3-yl]glyoxylamide D 24843 N-(Pyridin-4-yl)-(1-benzylindole-3-yl)-glyoxylamide D 24850 N-(4-Fluorophenyl)-[1-(3-pyridylmethyl)-indole-3-yl]glyoxylamide D 24851 N-(Pyridin-4-yl)-[1-(4-chlorobenzyl)-indole-3-yl]glyoxylamide D 25505 N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-indole-3-yl]glyoxylamide HCL [sic]


12. Use of N-substituted indole-3-glyoxylamides of the general formula 1or 1a and their physiologically tolerable acid addition salts for use inparticular in the case of pharmaceutical resistance and as a replacementfor antitumor agents which are no longer effective on account ofresistance formation in particular of the compounds D 24241N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)- indole-3-yl]glyoxylamide D 24843N-(Pyridin-4-yl)-(1-benzylindole-3-yl)- glyoxylamide D 24850N-(4-Fluorophenyl)-[1-(3-pyridylmethyl)- indole-3-yl]glyoxylamide D24851 N-(Pyridin-4-yl)-[1-(4-chlorobenzyl)- indole-3-yl]glyoxylamide D25505 N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)- indole-3-yl]glyoxylamide HCL[sic]


13. Use of N-substituted indole-3-glyoxylamides of the general formula 1or 1a and their physiologically tolerable acid addition salts for use inparticular in the case of pharmaceutical resistance in fixed or freecombination with known antitumor agents and as a replacement forantitumor agents which are no longer active on account of resistanceformation in particular of the compounds D 24241N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)- indole-3-yl]glyoxylamide D 24843N-(Pyridin-4-yl)-(1-benzylindole-3-yl)- glyoxylamide D 24850N-(4-Fluorophenyl)-[1-(3-pyridylmethyl)- indole-3-yl]glyoxylamide D24851 N-(Pyridin-4-yl)-[1-(4-chlorobenzyl)- indole-3-yl]glyoxylamide D25505 N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)- indole-3-yl]glyoxylamide HCL[sic]